Nootropic Peptides: Semax, Selank, Dihexa, and Noopept

Vendor catalogs sell Semax, Selank, Dihexa, and Noopept as a nootropic set. They are four different molecules. They do not share a receptor. They do not share a clinical evidence base.

This page stays with verified PubMed papers. It does not rank "which is strongest." It does not publish a protocol.

Research notice: These compounds are discussed for laboratory and literature comparison only. They are not approved for human consumption, medical treatment, or diagnosis in the United States based on the sources cited here.

At a glance

Vendor "P21" is not a fourth column. PubMed indexes a CNTF-derived tetrapeptide P021 (Ac-DGGL(A)G-NH2). That literature is summarized separately. A research vial labeled P21 is not verified as P021.

Semax

Semax is a heptapeptide analog of ACTH(4-10): Met-Glu-His-Phe-Pro-Gly-Pro.

Dolotov et al. (J Neurochem, 2006) found specific, reversible, calcium-dependent binding of tritiated Semax in rat basal-forebrain membranes (Kd 2.4 ± 1.0 nM; Bmax 33.5 ± 7.9 fmol/mg protein). Intranasal Semax in rats raised BDNF protein at 3 hours in basal forebrain, not cerebellum.

Dolotov et al. (Brain Res, 2006) reported that a single application in rats produced a maximal 1.4-fold increase in hippocampal BDNF protein, a 1.6-fold increase in trkB tyrosine phosphorylation, and 3-fold / 2-fold increases in exon III BDNF and trkB mRNA, with more conditioned-avoidance reactions. The authors proposed that cognitive effects involve the hippocampal BDNF/trkB system. Those are rodent findings. They are not a human BDNF claim.

Indexed clinical papers exist in Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova: Gusev, Skvortsova, Chukanova (2005) on cerebrovascular insufficiency; Gusev, Martynov, Kostenko et al. (2018) on ischemic stroke (PubMed title contains the journal's spelling "tretament"); Miasoedova, Skvortsova, Nasonov et al. (1999) on mechanisms in the acute period of ischemic stroke. Those papers document a clinical research program. This page does not extract numeric efficacy claims from them beyond what the indexed titles support in English, and it does not convert them into a treatment recommendation.

Pairwise chemistry versus Selank: Selank vs Semax.

Selank

Selank is a heptapeptide analog of tuftsin: Thr-Lys-Pro-Arg-Pro-Gly-Pro.

Zozulya et al. (2001) reported that Selank inhibited enzymatic hydrolysis of plasma enkephalin (IC50 15 micromolar) and was more potent than bacitracin and puromycin in that assay. Filatova et al. (2017) reported that Selank, GABA, and olanzapine affected expression of genes involved in GABAergic neurotransmission in IMR-32 cells. Do not upgrade those findings to "Selank is a benzodiazepine."

Zozulia, Neznamov, Siuniakov et al. (2008) compared Selank with medazepam in generalized anxiety and neurasthenia (62 patients: 30 Selank, 32 medazepam). Anxiolytic effects were described as similar; Selank was also described as having antiasthenic and psychostimulant effects. Medvedev, Tereshchenko, Israelian et al. (2014) compared Selank with phenazepam in 60 patients with phobic-anxiety and somatoform disorders. Those are published clinical comparisons in a Russian journal. They are not FDA trials.

Dihexa

Dihexa is N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, a metabolically stabilized angiotensin IV analog from the Wright/Harding group at Washington State.

McCoy et al. (2013) reported that dihexa reversed scopolamine-induced deficits in Morris water maze performance, showed synaptogenic activity, and was orally active in the scopolamine and aged-rat models they used. The Journal of Pharmacology and Experimental Therapeutics published a notice of concern on that paper in 2021 (PMID 34551989). This page cites the paper and the notice. It does not treat McCoy 2013 as settled human evidence.

Benoist et al. (2014) reported that the procognitive and synaptogenic effects of angiotensin IV-derived peptides, including this series, depend on activation of the hepatocyte growth factor/c-Met system. Wright and Harding (2015) reviewed HGF/c-Met as an Alzheimer-disease target. Those are rodent, cell, and review sources. No verified human dihexa RCT is in the sources below.

This site does not currently have a dihexa peptide page.

Noopept (GVS-111)

Noopept is N-phenylacetyl-L-prolylglycine ethyl ester, also called GVS-111. Gudasheva et al. (1997) identified cyclo-L-prolylglycine as the major metabolite in rat brain. Ostrovskaya et al. (2001) reported that the dipeptide retained nootropic activity after oral administration in rat avoidance tasks.

Ostrovskaya, Romanova, Barskov et al. (1999) reported memory-restoring and neuroprotective effects in a photochemical stroke model in rats, including a smaller infarct volume. Ostrovskaya, Gudasheva, Zaplina et al. (2008) reported that Noopept increased NGF and BDNF mRNA expression in rat hippocampus after acute administration; chronic treatment (28 days) did not produce tolerance in that readout and further increased the hippocampal neurotrophic effect. Cortical NGF/BDNF mRNA was below control after a single dose and only slightly increased BDNF after chronic treatment.

Neznamov and Teleshova published a comparison of Noopept and piracetam in patients with mild cognitive disorders of vascular and traumatic origin (2008 Russian-language paper; 2009 English translation in Neuroscience and Behavioral Physiology). That is a published clinical comparison. It is not an FDA trial, and this page does not convert it into a use instruction.

This site does not currently have a Noopept peptide page.

P021, and why "P21" is not a fifth verified column

Kazim, Blanchard, Dai et al. (2014) studied chronic oral treatment with a CNTF-derived peptidergic compound, P021 (Ac-DGGL(A)G-NH2), in 3xTg-AD mice. They reported effects on amyloid pathology, cognition, neurogenesis, and synaptic plasticity in that model. Baazaoui and Iqbal (2017) reported that P021 in the diet from 3 to 21 months prevented dendritic and synaptic deficits and reversed cognitive impairment in 3xTg-AD mice.

PubMed indexes P021. It does not, in the sources cited here, index a unique approved drug named P21. Vendor listings that say "P21" may or may not match Ac-DGGL(A)G-NH2. This page cannot certify a vial.

What is not claimed here

• A potency ranking of Semax versus Dihexa versus Noopept.
• Human BDNF elevation after Semax. The Dolotov papers are rat studies.
• Long-term safety of daily use. That dataset is not in the sources below.
• A stack of two nootropic peptides. There is no verified head-to-head RCT of Semax versus Selank, and no verified Semax-plus-Selank trial, in the sources cited.

Peptide pages, vendors, and calculator

• Semax peptide page
• Selank peptide page
• Vendors listing Semax: /stores?peptides=semax
• Vendors listing Selank: /stores?peptides=selank
• Reconstitution math (no dose advice): /tools/peptide-calculator?peptide=semax or Selank

Related: Selank vs Semax. Category hub: nootropic and mood peptides.

References

1. Gudasheva TA, Boyko SS, Ostrovskaya RU, et al. The major metabolite of dipeptide piracetam analogue GVS-111 in rat brain and its similarity to endogenous neuropeptide cyclo-L-prolylglycine. Eur J Drug Metab Pharmacokinet. 1997;22(3):245-252. PMID: 9358206. DOI: 10.1007/BF03189814.
2. Ostrovskaya RU, Romanova GA, Barskov IV, et al. Memory restoring and neuroprotective effects of the proline-containing dipeptide, GVS-111, in a photochemical stroke model. Behav Pharmacol. 1999;10(5):549-553. PMID: 10780261. DOI: 10.1097/00008877-199909000-00013.
3. Miasoedova NF, Skvortsova VI, Nasonov EL, et al. [Investigation of mechanisms of neuro-protective effect of semax in acute period of ischemic stroke]. Zh Nevrol Psikhiatr Im S S Korsakova. 1999;99(5):15-19. PMID: 10358912.
4. Zozulya AA, Kost NV, Sokolov OY, et al. The inhibitory effect of Selank on enkephalin-degrading enzymes as a possible mechanism of its anxiolytic activity. Bull Exp Biol Med. 2001;131(4):315-317. PMID: 11550013. DOI: 10.1023/a:1017979514274.
5. Ostrovskaya RU, Mirsoev TK, Romanova GA, et al. Proline-containing dipeptide GVS-111 retains nootropic activity after oral administration. Bull Exp Biol Med. 2001;132(4):959-962. PMID: 11782792. DOI: 10.1023/a:1013663126973.
6. Gusev EI, Skvortsova VI, Chukanova EI. [Semax in prevention of disease progress and development of exacerbations in patients with cerebrovascular insufficiency]. Zh Nevrol Psikhiatr Im S S Korsakova. 2005;105(2):35-40. PMID: 15792140.
7. Dolotov OV, Karpenko EA, Seredenina TS, et al. Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. J Neurochem. 2006;97 Suppl 1:82-86. PMID: 16635254. DOI: 10.1111/j.1471-4159.2006.03658.x.
8. Dolotov OV, Karpenko EA, Inozemtseva LS, et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Res. 2006;1117(1):54-60. PMID: 16996037. DOI: 10.1016/j.brainres.2006.07.108.
9. Zozulia AA, Neznamov GG, Siuniakov TS, et al. [Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia]. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(4):38-48. PMID: 18454096.
10. Ostrovskaya RU, Gudasheva TA, Zaplina AP, et al. Noopept stimulates the expression of NGF and BDNF in rat hippocampus. Bull Exp Biol Med. 2008;146(3):334-337. PMID: 19240853. DOI: 10.1007/s10517-008-0297-x.
11. Neznamov GG, Teleshova ES. [A comparative study of noopept and piracetam in the treatment of mild and moderate cognitive impairment in patients with organic brain diseases of vascular and traumatic origin]. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(3):33-42. PMID: 18697252.
12. Neznamov GG, Teleshova ES. Comparative studies of Noopept and piracetam in the treatment of patients with mild cognitive disorders in organic brain diseases of vascular and traumatic origin. Neurosci Behav Physiol. 2009;39(3):311-321. PMID: 19234797. DOI: 10.1007/s11055-009-9128-4.
13. McCoy AT, Benoist CC, Wright JW, et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013;344(1):141-154. PMID: 23055539. DOI: 10.1124/jpet.112.199497.
14. Benoist CC, Wright JW, Bule-Ghogare JM, et al. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014;351(2):390-402. PMID: 25187433. DOI: 10.1124/jpet.114.218735.
15. Kazim SF, Blanchard J, Dai CL, et al. Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2014;71:110-130. PMID: 25046994. DOI: 10.1016/j.nbd.2014.07.001.
16. Medvedev VE, Tereshchenko ON, Israelian AIu, et al. [A comparison of the anxiolytic effect and tolerability of selank and phenazepam in the treatment of anxiety disorders]. Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(7):17-22. PMID: 25176261.
17. Wright JW, Harding JW. The brain hepatocyte growth factor/c-Met receptor system: a new target for the treatment of Alzheimer's disease. J Alzheimers Dis. 2015;45(4):985-1000. PMID: 25649658. DOI: 10.3233/JAD-142814.
18. Filatova E, Kasian A, Kolomin T, et al. GABA, Selank, and Olanzapine Affect the Expression of Genes Involved in GABAergic Neurotransmission in IMR-32 Cells. Front Pharmacol. 2017;8:89. PMID: 28293190. DOI: 10.3389/fphar.2017.00089.
19. Baazaoui N, Iqbal K. Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound. Alzheimers Res Ther. 2017;9(1):45. PMID: 28655344. DOI: 10.1186/s13195-017-0273-7.
20. Gusev EI, Martynov MY, Kostenko EV, et al. [The efficacy of semax in the tretament of patients at different stages of ischemic stroke]. Zh Nevrol Psikhiatr Im S S Korsakova. 2018;118(3 Pt 2):61-68. PMID: 29798983. DOI: 10.17116/jnevro20181183261-68.
21. Journal of Pharmacology and Experimental Therapeutics. Notice of Concern: McCoy AT, Benoist CC, Wright JW, Kawas LH, Bule-Ghogare JM, Zhu M, Appleyard SM, Wayman GA, and Harding JW (2013) Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents. J Pharmacol Exp Ther. 2021;378(3):313. PMID: 34551989. DOI: 10.1124/jpet.112.199497concern.